Antigen binding to the membrane IgR initiates the activation and maturation of the antigen-specific B cells in the peripheral lymphoid organs (Rajewsky, Nature (Lond.)., 381:751-758, 1996; Sakaguchi et al., Adv. Immunol. 54:337-392, 1993). B cells enter the outer periarterial lymphoid sheath (PALS) (Rajewsky, Nature (Lond.)., 381:751-758, 1996) and initiate costimulus-dependent interactions with specific Th cells and interdigitating dendritic cells within 48 h after immunization (MacLennan, Annu. Rev. Immunol. 12:117-139, 1994; Liu et al., Immunol. Rev. 156:111-126, 1997). Antigen-driven B cells proliferate in the outer PALS and then undergo further activation in the lymphoid follicles to establish the germinal center (herein sometimes abbreviated as GC) (Han et al., J. Immunol. 155:556-567, 1995; Jacob et al., J. Exp. Med. 176:679-687, 1992; Kelsoe, Immunity 4:107-111, 1996). Such B cells mature into large slg− centroblasts that rapidly move through the cell cycle to form the dark zone and further mature into centrocytes that express a unique surface character of PNA+B220+slgM+slgD−CD38− in the light zone of the GC (Kosco-Vilbois et al., 1997. Immunol. Today 18:225-230, 1997; Kelsoe, Immunol. Today 16:324-326, 1995; Oliver et al., J. Immunol. 158:1108-1115, 1997).
Centrocytes presumably undergo the processes of either apoptosis or affinity maturation of immunoglobulin V regions and the change process of class switching toward the lgG class antigen. Some centrocytes survive for a longer period in the lymphoid compartment as memory B cells. The other centrocytes probably migrate to the marginal zone of the GC and receive further antigenic stimulation and costimulatory signals through B cell activation molecules, such as CD40 and CD38, and receptors for various B cell stimulatory cytokines (Gray et al., J. Exp. Med., 180:141-155, 1994; Foy et al., J. Exp. Med., 180:157-163, 1994). Antigen-specific B cells further stimulated in this area probably migrate into the interstitial region of the spleen (called red pulp), where various kinds of other immune-competent cells may interact with antigen-driven B cells. Histochemical analysis in several autoimmune mice identified unique antibody-producing cells in this area which appear as plasma cells or aberrant plasma cells called Mott cells (Tarlinton et al., Eur. J. Immunol. 22:531-539, 1992; Jiang et al., J. Immunol., 158:992-997, 1997).
Auto immunity is a phenomenon in which the impairment of self/nonself discrimination occurs frequently in the antigen-specific lymphocytes (Theofilopoulos, Immunol. Today, 16:90-98, 1995). The immune systems of various autoimmune diseases show the combinatory mechanism involving T cells and B cells (Theofilopoulos et al., Adv. Immunol., 37:269-290, 1985; Okamoto et al., J. Exp. Med. 175:71-79, 1992; Reininger et al., J. Exp. Med., 184:853-861, 1996; Theofilopoulos, et al., Immunol. Rev. 55:179-216, 1981; Watanabe-Fukunaga et al., Nature (Lond.)., 356:314-317, 1992; Takahashi et al., Cell, 76:969-976, 1994; Shlomchick et al., Nature (Lond.). 328:805-811, 1987).
NZB and NZW are the strains characterized by multiple genetic factors generating the severe autoimmune state of SLE as (NZB×NZW)F1 mice (Theofflopoulos et al., Adv. Immunol., 37:269-290, 1985; Okamoto et al., J. Exp. Med., 175:71-79, 1992; Reininger et al., J. Exp. Med., 184:853-861, 1996; Theofilopoulos et al., Immunol. Rev., 55:179-216, 1981). NZB mice spontaneously generate the state of autoimmunity with the anti-red blood cell antibody that causes an autoimmune hemolytic anemia (Okamoto et al., J. Exp. Med., 175:71-79, 1992). NZW mice show an insidious autoimmune phenomenon (Reininger et al., J. Exp. Med. 184:853-861, 1996). The SLE state of (NZB×NZW)F1 mice is apparently caused by multiple genetic factors associated with T and B cells (Theofilopoulos et al., Immunol. Rev., 55:179-216, 1981). NZB mice show an apparent abnormality of B cells, but the molecular mechanism of the abnormal B cell activation in NZB mice remains to be elucidated.